A so far unrecognized mechanism of acetaminophen hepatotoxicity

Acetaminophen (APAP) is one of the most frequently used antipyretic and analgesic drugs. Overdoses lead to hepatotoxicity due to metabolic activation by the CYP450 enzymes, mainly CYP2E1, and excessive formation of the toxic intermediate N-acetyl-p-benzoquinone imine. Despite the extensive knowledge of the mechanism of APAP hepatotoxicity, the only approved therapy is the administration of N-acetylcysteine, which is limited by a narrow time window. In this study, the role of bile acids in APAP-induced liver injury was investigated. For this purpose, a mouse model of APAP-induced hepatotoxicity was used. Alterations in bile acid transport and canalicular morphology were evaluated by intravital two-photon imaging. Key findings were followed up by matrix‐assisted laser desorption ionization (MALDI MSI) imaging, clinical chemistry, histopathology, and immunohistochemistry. The results revealed that early after APAP intoxication, a breach of the bile-blood barrier occurred in the pericentral compartment of the liver lobule, which led to recirculation of bile acids between bile canaliculi, sinusoids, and hepatocytes. This exposed the pericentral hepatocytes to very high concentrations of bile acids. Interestingly, this transient stage of cholestasis occurred before the increase of transaminases activity in the blood, which excludes that this increase in bile acid concentrations is because of liver dysfunction following hepatocyte death. In order to study if the observed transient cholestasis is a key event relevant for the subsequent hepatocyte death, we performed an experiment to block the hepatocyte uptake of bile acids from the sinusoidal blood. For this purpose, the NTCP inhibitor Myrcludex B (5 mg/kg, i.v.) was administered to Oatp knockout mice; simultaneously, the mice received a toxic dose of APAP (300 mg/kg), and then the liver damage was evaluated 24 hours later. Interestingly, blocking the sinusoidal uptake of bile acids strongly reduce APAP hepatotoxicity in comparison to the wild-type mice. In conclusion, the results demonstrate a transient stage of cholestasis which is a key event in the pathogenesis of APAP-induced hepatotoxicity. Therapeutic exploitation of this mechanism by blocking the sinusoidal uptake transporters of bile acids strongly ameliorated APAP-induced liver injury.

Publication History

Article published online:
04 January 2021